Process for suppressing the tremor of parkinson&#39;s syndrome

ABSTRACT

THE TREMOR OF PARKINSONS&#39;&#39;S SYNDROME IN MAMMALS IS SUPPRESSED BY THE ADMINSTRATION OF A COMPIUND OF THE FORMULA:   2-(4-R-PIPERAZIN-1-YL)-QUINOLINE   IN WHICH R IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF H AND CH3, AND NONTOXIC PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF. THESE COMPOUNDS MAY BE UTILIZED IN CONJUNCTION WITH PHARMACEUTICALLY ACCEPTABLE VEHICLES THEREFOR.

United States Patent 3,743,732 PROCESS FOR SUPPRESSING THE TREMOR OFPARKINSONS SYNDROME Rodolfo Rodriguez, Mexico City, Mexico, assignor toMiles Laboratories, Inc., Elkhart, Ind. No Drawing. Filed Feb. 14, 1972,Ser. No. 226,238 Int. Cl. A61k 27/00 US. Cl. 424-250 3 Claims ABSTRACTOF THE DISCLOSURE The tremor of Parkinsons syndrome in mammals issuppressed by the administration of a compound of the formula:

N N-R in which R is a member selected from the group consisting of H andCH and nontoxic pharmacologically acceptable acid addition saltsthereof. These compounds may be utilized in conjunction withpharmaceutically acceptable vehicles therefor.

This invention relates to a process for suppressing Parkinson-likesyndrome of a mammal by the administration to such mammal of a tremorsuppressing amount of a compound of the formula:

wherein R is selected from the group consisting of H and CH and nontoxicpharmacologically acceptable acid addition salts thereof.

The management of Parkinsons disease is a complex problem in which drugtherapy plays a major role. For many years the most widely usedtherapeutic agents were belladonna alkaloids such as atropine andscopolamine, and although some neurologists still regard these productsas useful agents, they have been largely replaced by syntheticanticholinergic compounds such as trihexyphenidyl, benztropine,cycrimine, procyclidine and biperiden. Certain drugs that are classifiedprimarily as antihistaminics such as diphenhydramine, orphenadrine andchlorphenoxamine are also used in Parkinsons disease, but since thesealso exhibit significant anticholinergic actions, it is probable thatthe underlying attribute responsible for their therapeutic activity isrelated to this effect.

Recently, the dopamine precursor, levodopa, has been shown to beeffective in controlling Parkinsonism when administered in adequatedoses over extended periods of time. Although both anticholinergicagents and levodopa are beneficial in alleviating the primary symptomsof Parkinsonism, their clinical use is limited by the frequency withwhich they elicit untoward side elfects. Thus, anticholinergic drugs mayproduce dry mouth, blurred vision, photophobia, constipation, urinaryretention and tachychardia, while nausea, anorexia, vomiting, attemptedsuicide, agitation, confusion, restlessness, hallucinations, delirium,choreiform movements, palpitations, postural hypotension, flushing andphlebitis may occur with levodopa.

An object of this invention is to provide a new process for controllingextrapyramidal symptoms. This effect is desirable in patients sufferingfrom either ideopathic or postencephalitic Parkinsonism.

3,743,732 Patented July 3, 1973 "ice The active ingredient of themedication used for the novel process of the present invention has thefollowing structural formula:

(lisp- N N NH CHOOCH CHOOOH Although 2-bromoquinoline has been utilizedin this general equation, other 2-haloquinolines, such as2-chloroquinoline, may be similarly used with equally desirable results.

The active ingredient used in the novel process of this invention may bein the form of the free base and is preferably in the form of a nontoxicpharmacologically acceptable acid addition salt thereof. These acidaddition salts may be prepared from mineral acids such as halogen acidsor sulfuric acid, or organic acids such as citric acid, maleic acid,oxalic acid and other similar acids. Additional examples of thepreparation of these acids will be presented in the subsequent detailedexamples.

Medications may be prepared for use in the novel process of thisinvention including, as an active ingredient, at least one of thecompounds of Formula I. These medications may be conveniently preparedby combining the active ingredient with a pharmaceutical vehicle havingcomponents selected from the fillers, carriers, extenders, excipientsand the like, generally used in pharmaceutical formulations. Medicationsmay be prepared in the solid state as tablets or capsules or in theliquid state as suspensions or solutions. Similar dosage forms suitablefor oral, parenteral, intramuscular, subcutaneous, intravenous or otherconvenient routes of administration may also be provided. Thepharmaceutical vehicle may also include common diluents or tabletingadjuncts such as cellulose powder, cornstarch, magnesium sterate,calcium sulfate, talc and such, used according to acceptedpharmaceutical manufacturing practices. Unit dosages (a specific weight,such as mg. or g.) of active ingredient in a medication may be varied sothat an adequate amount is present to provide the desired therapeuticdose which produces a particular therapeutic effect without untowardside eifects. Unit dosages of between about 1 and 30 mg. per tablet,capsule and so forth, are beneficially used for oral administration ofthe medication.

The therapeuitic dose, administered using the unit dosages describedabove, will depend upon the condition of the patient. Beneficially,daily doses ranging between about and 90 mg./kg. per day are consideredsafe and readily indicative of a required therapeutic dose.

The inveniton will be further understood by reference to the followingexamples which are provided as illustrations and are not intended to beconstrued as limitations upon the invention which is properly set forthin claims appended hereto.

EXAMPLE -1 Preparation of 1-(2-quinolyl)piperaz.ine

A mixture of 2-chloroquinoline (477 g., 2.92 moles), piperazine (503 g.,5.83 moles) and 750 ml. of toluene was stirred and heated under refluxfor 6 hours. The mixture was cooled in an ice bath and 750 ml. of waterwas added with stirring. Then the mixture was acidified withconcentrated hydrochloric acid. The insoluble 1,4-bis(2-quinolyl)piperazine was removed by filtering the slightly warm mixturethrough infusorial earth. The filtrate was diluted with 2 liters ofwater which dissolved most of the solid which had separated out. Thetoluene layer was separated and the aqueous portion was extracted with alittle ether. Then the aqueous mixture was treated with decolorizingcharcoal and filtered through infusorial earth. The solution was madealkaline with sodium hydroxide. The solid free base was collected on afilter and washed with water. The crude material was dissolved in about1 liter of hot ethanol and the solution was clarified with charcoal.Then the mixture was diluted with 2 liters of water. The white crystalswhich separated on cooling were collected, washed with water and driedin an oven at 150 F. The l-(2-quinolyl)piperazine (437 g., 70.2 percent)melted at 81 83 C.

Analysis.Calcd. for C H N (percent): N (basic), 13.14; N (total), 19.70.Found (percent): N (basic), 12.93; N (total), 19.72.

EXAMPLE 2 Preparation of 1-(2-quinolyl)piperazine maleate The free basewas dissolved in 4200 ml. of hot 2-propanol and a solution of maleicacid (239 g., 2.06 moles) in 1500 ml. of hot 2-propanol was added in oneportion with stirring. The stirring was continued, while the mixture wascooled in an ice bath. Then the salt was collected, washed with2-propanol and dried in the oven at 150 F. The 1-(2- quinolyl)piperazinemaleate amounted to 650 g. (95.8 percent based on the free base) andmelted at 174175 C.

Analysis.Calcd. for C H N O (percent): N (basic), 8.51; N (total) 12.75;N.E., 164.7. Found (percent): N (basic), 8.50; N (total), 12.70; N.E.165.3.

EXAMPLE 3 Preparation of 1-(2-quinolyl)-4-methylpiperazine A mixture of2-chloroquinoline (81.8 g., 0.5 mole), l-methylpiperazine (100.2 g., 1mole) and 100 ml. of toluene was heated to boiling. An exothermicreaction set in, but it was necessary to apply additional heat tomaintain a vigorous boiling. After about 30 minutes the spontaneousreaction was over, and the mixture was heated under reflux for 2 hourslonger. A dark syrupy material separated out.

The mixture was stirred and cooled, during which 300 ml. of watercontaining 100 ml. of concentrated hydrochloric acid was added. A smallamount of insoluble solid material was removed by filtration and washedwith ether and water. The aqueous portion of the filtrate and washingswas separated and clarified with charcoal. An excess of a saturatedaqueous solution of sodium hydroxide was added to the filtrate. The freebase was collected, washed with Water and dried at 50 C. The crudeproduct (104.5 g., melted at 111 C.

The crude free base was dissolved in hot ethanol, and the solution wasclarified with charcoal. The filtrate and washings were concentrated byevaporation and diluted with hot water to incipient cloudiness. Thecrystals which formed on cooling and scratching were collected, washedwith water and dried at 100 C. The cream-colored free base (102 g., 90%)melted at 111-112 C.

Analysis.Calcd. for C H N (percent): N (basic), 6.16. Found (percent): N(basic), 6.08.

EXAMPLE 4 Preparation of 1-(2-quinolyl)-4-methylpiperazine maleate1-(2-quinolyl)-4-methylpiperazine (101.0 g., 0.445 mole) in 300 ml. ofhot 2-propanol was treated with a solution of maleic acid (53.6 g., 0.46mole) in 200 ml. of hot 2-propanol. Crystals began to form immediately.After cooling in an ice bath the crystals were collected, washed withethyl acetate and dried at 100 C. The crude salt (146.0 g., M.P. 161 C.)was dissolved in about 2 liters of boiling 2-propanol. The solution wasconcentrated by evaporation until crystals began to form. The mixturewas cooled and the salt was collected. The crystals were washed withethyl acetate and dried at 100 C. The product amounted to 141.5 g.(93%).

Analysis.-Calcd. for C I-I N .C H O (percent): N (basic), 8.16; N(total), 12.24; N.E., 171.7. Found (percent): N (basic), 8.14; N(total), 12.32; N.E., 173.3.

EXAMPLE 5 Pharmacological activity of 1-(2-quino1yl)piperazine and1-(2-quinolyl)-4-methylpiperazine The anti-Parkinson activity of1-(2-quinolyl)piperazine and 1-(2-quinolyl)-4-methylpiperazine wasassessed by its ability to antagonize tremorine-induced tremor in miceand was compared with that of the reference compounds atropine sulfate,trihexyphenidyl hydrochloride and levodopa. For this test, graded dosesof test drugs were given orally to groups of 10 mice 15 minutes beforethe intraperatoneal injection of tremorine (20 mg./kg.). This dosecauses severe tremor, together with profuse salivation, lachrymation anddiarrhea. The presence of tremor was determined 30 minutes afteradministration of tremorine by an observer who was unaware of thetreatment the animals had received. Animals which did not show tremor ofthe head during a 1 minute observation period were considered protected.The proportion of mice protected at each dose level was used to estimateED s. The results observed in this experiment are presented in the tablewhich follows, wherein Compound A is 1-(2- quinolyl)piperazine maleateand Compound B is 1-(2- quinolyl) -'4-methylpiperazine.

Mg./kg., p.o.

Drugs ED 50 L as N Compound A 5.0 3. 3-7. 5 40 Compound B 15. 5 9. 425.6 5O Atropine 8. 4 5. 6-12. 6 b0 Trihexyphenidyl. 7. 0 4. 211. 5 50Levodopa 375. 0 279. 8-502. 5 50 evaluation of tremor was carried out 15minutes after injection of the tremorigenic substance. The activeingredients of these compositions antagonized oxotremorine-inducedtremor in a dose-response fashion. The ED and 95% confidence limits forCompounds A and B were 8.0 (3.8-l6.8) mg./kg. and 18.5 (10243.7)mg./kg., respectively.

What is claimed is:

1 A process of suppressing the tremor of Parkinsons syndrome in a mammalcomprising administering to said mammal a tremor suppressing amount of acompound selected from the group consisting of 1-(2-quinolyl)piperazine,1-(2 quinolyl)-4-piperazine, and a pharmacologi- 6 cally acceptable acidaddition salt of said compound.

2. The process of claim 1 in which said compound is1-(2-quinolyl)piperazine.

3. The process of claim 1 in which said compound is 5 l- (2- quinolyl)-4-methylpiperazine.

References Cited UNITED STATES PATENTS STANLEY J. FRIEDMAN, PrimaryExaminer UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PatentNo. 3 732 Dated ug 10 1973 Inventor(s) Rodolfo Rodriguez It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 5, line 13, Qjlaim l:

l-(Z-quinOlYl)-4-piperazine. should reed 1-(2-quinolyl)-4'methylpiperazine-.

Signed end sealed this 20th day of Novem ber' 1973.

(SEAL) Atte st EDWARD M.FLETCHER,JR. V RENE D. 'I'EGTMEYER ActingCommissioner of Patents Attesting Officer USCOMM-DC 60376-P69 U,SGOVERNMENT PRINTING OFFICE I I969 O366'33l FORM PO-105O (10-69)

